PROJECT SUMMARY Although anti-retroviral therapy (ART) enhances life expectancy and overall quality of life (QoL), HIV-infected individuals are increasingly vulnerable to non-AIDS-related diseases including HIV-associated neurocognitive disorders (HAND) . Inflammation, particularly activated monocytes/macrophages (M/M), is considered to be a primary mechanism in the pathogenesis of HAND. Tobacco use may further exacerbate inflammation and thus increase the incidence and severity of HAND. Conversely, nicotine alone has anti-inflammatory effects, mainly through activation of the ?7 nicotinic receptors (nAChRs) suggesting that stimulating the cholinergic pathway may be a novel therapeutic target to suppress inflammation and reverse or prevent neurocognitive deficits in HIV-1 infection. Consistent with RFA-DA-17-020, this proposal seeks to evaluate a pharmacological treatment that targets cholinergic function, improves neurocognition, and attenuates inflammation, to probe the interaction between inflammation, nicotinic receptors and smoking in HIV-infected people, and potentially mitigate HIV-associated adverse health consequences, including HAND. We will utilize galantamine (GAL), an FDA-approved procognitive medication that increases endogenous levels of acetylcholine by inhibiting the acetylcholinesterase enzyme and acting as a positive allosteric modulator of the ?7 nAChRs. Based on evidence that inflammation is implicated in the pathogenesis of HAND, and that GAL has anti-inflammatory properties, we hypothesize that: (1) nAChR modulation by GAL will reduce chronic residual inflammation and improve neurocognition in ART-treated HIV infection; and (2) that these effects will be larger among chronic smokers (vs. nonsmokers) due to the synergistic effects of nicotine and GAL. In this double-blind, placebo- controlled crossover study, HIV-infected individuals (N=120; 60 smokers, 60 nonsmokers) will be randomized to 12 weeks of GAL or placebo, followed by a 4-week washout, then 12 weeks of GAL or placebo (arms switched). All subjects will be stable on ART and the GAL dose will follow FDA guidelines. At the beginning and end of each treatment phase, M/M and T cell activation markers, soluble inflammatory biomarkers, and viral load will be assessed. Monocyte transcriptomics will also be assessed on a subset of the sample (n=60; 30/group). Neurocognition and clinical outcomes (e.g., chronic fatigue, QoL) will be measured at baseline and at 4-week intervals during each treatment phase. The primary outcomes are M/M and T cell activation (CD16, CD163, and CCR2 expression; plasma CCL2 [MCP-1] and sCD14; CD38/HLA-DR on CD8 cells) and neurocognitive performance (processing speed, verbal learning/memory, executive function). Exploratory outcomes include monocyte gene expression patterns and broad plasma cytokine analysis. This innovative approach will provide mechanistic insight into the interactions among nAChR activation, HIV immune activation and pathogenesis, and tobacco use and has translational and therapeutic implications that could improve health outcomes and QoL among HIV-infected individuals.